EP1121372B1 - Adenine-derivate - Google Patents

Adenine-derivate Download PDF

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EP1121372B1
EP1121372B1 EP99946382A EP99946382A EP1121372B1 EP 1121372 B1 EP1121372 B1 EP 1121372B1 EP 99946382 A EP99946382 A EP 99946382A EP 99946382 A EP99946382 A EP 99946382A EP 1121372 B1 EP1121372 B1 EP 1121372B1
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compound
alkyl
amino
tetrahydro
formula
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EP1121372A1 (de
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Sandra Marina Pfizer Central Research MONAGHAN
Simon John Pfizer Central Research MANTELL
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Pfizer Ltd
Pfizer Inc
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Pfizer Ltd
Pfizer Inc
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Priority claimed from GBGB9822702.8A external-priority patent/GB9822702D0/en
Priority claimed from GBGB9825383.4A external-priority patent/GB9825383D0/en
Priority claimed from GBGB9908931.0A external-priority patent/GB9908931D0/en
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    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Definitions

  • the present invention relates to certain adenine derivatives that are selective, functional agonists of the human adenosine A2a receptor, to their preparation, and to compositions and uses thereof.
  • the compounds and compositions may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
  • Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, such as superoxide anion radicals (O 2 - ), and granule products, such as human neutrophil elastase (HNE), amongst other inflammatory mediators.
  • reactive oxygen species such as superoxide anion radicals (O 2 - )
  • HNE human neutrophil elastase
  • LTB 4 is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O 2 - and HNE adversely affect pulmonary extracellular matrix.
  • the A2 receptor subtype mediating many of these responses (O 2 - and LTB 4 /HNE. release and cell adhesion) is established as A2a.
  • the A2 subtype (A2a or A2b) mediating the other effects remains to be established.
  • Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than non-selective adenosine receptor agonists because interaction with other receptor subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury.
  • WO 88/03147 A discloses adenosine derivatives in which the 2-position of the adenine ring is not substituted. Said derivatives are used in the treatment of cardiovascular diseases.
  • adenine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor.
  • the present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage) -induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.
  • ARDS adult respiratory distress syndrome
  • bronchitis chronic bronchitis
  • cystic fibrosis asthma
  • emphysema bronchiectasis
  • chronic sinusitis and rhinitis chronic sinusitis and rhinitis.
  • the present compounds may also be used in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacterpylori-gastritis, non- Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
  • the present invention provides a compound of formula (I): wherein R 1 is alkyl or cyclopropylmethyl; R 2 is phenyl-alkylene or naphthyl-alkylene, said alkylene chain being optionally further substituted by phenyl or naphthyl, each phenyl or naphthyl being optionally substituted by one or more substituents each independently selected from alkyl, alkoxy, halo and cyano; n is 1 or 2; A is NR a , NR a C(O), NR a C(O)NR a , NR a C(O)O, OC(O)NR a , C(O)NR a , NR a SO 2 , SO 2 NR a , O, S or SO 2 ; R a is H, alkyl or benzyl optionally ring-substituted by one or more substituents each independently selected from alkyl, alkoxy
  • the present invention provides a compound of the formula (I) wherein R 1 is C 1 -C 6 alkyl or cyclopropylmethyl; R 2 is phenyl-(C 1 -C 6 )-alkylene or naphthyl-(C 1 -C 6 )-alkylene, said C 1 -C 6 alkylene chain being optionally further substituted by phenyl or naphthyl, each phenyl or naphthyl being optionally substituted by one or more substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo and cyano; n is 1 or 2; A is NR a , NR a C(O), NR a C(O)NR a , NR a C(O)O, OC(O)NR a , C(O)NR a , NR a SO 2 , SO 2 NR a , O, S or SO 2
  • the present invention provides a compound of the formula (I) wherein R 1 is alkyl or cyclopropylmethyl; R 2 is phenyl-alkylene or naphthyl-alkylene where the alkylene chain may be substituted with methyl, ethyl, phenyl or naphthyl; n is 1 or 2; and A is NR a , NR a C(O), NR a C(O)NR a , NR a C(O)O, OC(O)NR a , C(O)NR a , NR a SO 2 , SO 2 NR a , O, S or SO 2 , in which R a is H or alkyl; R 3 is a group of the formula -(CH 2 ) p -R p -B, wherein p is 0, 1 or 2; R p is a bond, or is alkylene, optionally alkyl-substituted cycloal
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl, alkoxy and alkylene groups containing the requisite number of carbon atoms can be unbranched- or branched-chain.
  • alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
  • alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.
  • alkylene examples include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkylene examples include cyclopropylene, cyctobutylene, cyclopentylene, cyclohexylene and cycloheptylene.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p -toluenesulphonate and pamoate salts.
  • Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
  • the pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
  • a compound of the formula (I) may contain one or more additional asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms.
  • the present invention includes the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof.
  • Separation of diastereoisomers and cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof.
  • An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • said optionally-substituted, fully- or partially-saturated or - unsaturated, mono- or bicyclic, heterocyclic group which is linked to R p by a ring carbon atom, preferably has from 4 to 12 ring atoms, preferably from 4 or 5 to 10 ring atoms, each independently selected from C, N, O and S. More preferably, said group has ring atoms selected from 1 to 4 N atoms, 1 or 2 O and 1 or 2 S atoms, with the remaining ring atoms being C atoms.
  • said group has from 1 to 4 ring N atoms, or 1 or 2 ring N atoms and 1 O or 1 S ring atom, or 1 O or 1 S ring atom, with the remaining ring atoms being C atoms.
  • Examples of fully-unsaturated, that is heteroaryl, groups include imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and quinoxalinyl.
  • Examples of partially-saturated or-unsaturated heterocyclic groups include 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.
  • Examples of fully-saturated heterocyclic groups include azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, morpholinyl and piperazinyl.
  • Said heterocyclic groups can be optionally substituted by one or more substituents each independently selected from R 5 , -OR 5 , halo, oxo, hydroxy, cyano, -COR 5 , -COOH, -COOR 5 , -CONH 2 , -CONHR 5 , -CONR 5 R 5 , amino, -NHR 5 , -NR 5 R 5 , -SO 2 R 5 , -SO 2 NH 2 , -SO 2 NHR 5 , -SO 2 NR 5 R 5 , -NHCOR 5 , -NR 5 COR 5 , - NHSO 2 R 5 , -NR 5 SO 2 R 5 and pyridinyl, wherein R 5 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or naphthyl, each optionally substituted by C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy
  • R 1 is C 1 -C 6 alkyl.
  • R 1 is methyl.
  • R 2 is phenyl-(C 1 -C 6 )-alkylene, said C 1 -C 6 alkylene chain being optionally further substituted by phenyl.
  • R 2 is 2-phenylethyl, said ethyl chain being optionally further substituted by phenyl.
  • R 2 is 2-phenylethyl or 2,2-diphenylethyl.
  • R 2 is 2,2-diphenylethyl.
  • A is NR a , NR a C(O), NR a C(O)O, C(O)NR a , NR a SO 2 , SO 2 NR a , O, S or SO 2 .
  • A is NR a or NR a SO 2 .
  • R a is H, C 1 -C 6 alkyl or benzyl optionally ring-substituted by one or more C 1 -C 6 alkoxy substituerits.
  • R a is H, methyl, 2-methylprop-1-yi or methoxybenzyl.
  • R a is H, methyl, 2-methylprop-1-yl or 2-methoxybenzyl.
  • R 3 is H, C 1 -C 6 alkyl optionally substituted by C 3 -C 7 , cycloalkyl, C 1 -C 6 alkoxy, amino, - NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -CONH 2 , -CONH(C 1 -C 6 alkyl), -CON(C 1 -C 6 alkyl) 2 , phenyl (optionally substituted by halo, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-(C 1- C 6 )-alkylene, amino-(C 1 -C 6 )-alkylene, cyano or piperidinyl (optionally substituted by C 1 -C 6 alkyl, halo-(C 1 -C 6 )-alkyl or halo-(C 1 -C 6 )-alkanoyl)), piperidinyl or t
  • R 3 is H, methyl, n-propyl, i-propyl, 2-methylprop-1-yl, 2,2-dimethylprop-1-yl, n-butyl, t-butyl, pentan-3-yl, cyclopentyl, cyclohexyl, 4-(isopropyl)cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-(N,N-dimethylcarbamoyl)ethyl, N,N-' (diisopropyl)carbamoylmethyl, 2-(N-t-butylcarbamoyl)ethyl, phenyl, benzyl, 4-chlorobenzyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 4-(isopropoxy)benzyl, 2-methoxymethylbenzyl
  • R 3 is phenyl, cyclohexyl, 5-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl, 2-methylprop-1-yl, i-propyl, 2-methoxybenzyl or N,N-(diisopropyl)carbamoylmethyl.
  • -A-R 3 is amino, isopropylamino, pentan-3-ylamino, 2-methylprop-1-ylamino, di(2-methylprop-1-yl)amino, N-cyclohexyl-N-methylamino, 2-methoxyethylamino, 2-(N,N-dimethylcarbamoyl)ethylamino, N,N-(diisopropyl)carbamoylmethylamino, 2-(N-t-butylcarbamoyl)ethylamino, cyclopentylamino, cyclohexylamino, 4,4-dimethylcyclohexylamino, 4-(isopropyl)cyclohexylamino, 4-methoxycyclohexylamino, cis-4-methoxycyclohexylamino, trans-4-methoxycyclohexylamino, 4-benzylaminocycl
  • -A-R 3 is phenylsulphonamido, cyclohexylamino, 5-methyl-1,2,3,4-tetrahydroisoquinolin-8-ylsulphonylamido, 2-methylprop-1-ylamino, i-propylamino, 2-methoxybenzylamino, N,N-(diisopropyl)carbamoylmethylamino or 2-methylprop-1-ylsulphonamido.
  • Preferred examples of compounds of the formula (I) include those of the Examples section hereafter, including any pharmaceutically acceptable salts thereof.
  • the compounds of the formula (I) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.
  • R 1 , R 2 , R 3 , A and n are as previously described for a compound of the formula (I) unless otherwise stated.
  • Compounds of formula (I) may be prepared by reduction of the corresponding compound of formula (IIA): wherein q is n-1, using a reducing agent, such as by catalytic hydrogenation (e.g . with palladium-on-carbon), in a suitable solvent such as an alcohol ( e.g . ethanol), optionally in the presence of ammonia, to form the corresponding compound of formula (IA), which is a compound of formula (I) wherein A is -NH and R 3 is -H: and thereafter optionally converting the compound of formula (IA) so prepared to another compound of formula (I) or salt thereof.
  • a reducing agent such as by catalytic hydrogenation (e.g . with palladium-on-carbon)
  • a suitable solvent such as an alcohol (e.g . ethanol)
  • ammonia optionally in the presence of ammonia
  • a suitable method to prepare compounds of formula (I) wherein A is -NHCO- or -NHSO 2 comprises reaction of the corresponding compound of formula (IA) with a compound of formula X-(CO or SO 2 )-R 3 wherein X is a leaving group, such as halo (especially chloro), in the presence of an acid acceptor, such as triethylamine, and in a suitable inert solvent, such as tetrahydrofuran (THF) or dichloromethane.
  • 2,6-lutidine may be utilised as both the acid acceptor and the solvent.
  • Other standard methods may be used to convert the (CH 2 ) n -NH 2 group to those wherein A is -NR a (e.g., using a compound of the formula halo-R 3 , where halo is preferably chloro, or where p is 2, R p is a bond and B is -CONR b R b , a suitable acrylamide derivative), -NR a CO, -NR a CONR a , -NR a COO (e.g., by reaction with a suitable dicarbonate derivative) and -NR a SO 2 .
  • the corresponding compound of formula (IIA) may be subjected to nitrile hydrolysis, using standard methods, followed by protection of the reactive hydroxy/carboxyl groups to form the corresponding protected ester of formula (IIB): wherein P is a protecting group, preferably tert -butyldimethylsilyl chloride (TBDMS); R d is H or alkyl; and q is as defined for formula (IIA).
  • TDMS tert -butyldimethylsilyl chloride
  • R d is H or alkyl
  • q is as defined for formula (IIA).
  • the compound of formula (IIB) may be reduced using a reducing agent, such as a metal hydride (e.g . Lithium borohydride), to form the corresponding compound of formula (IB), which is a protected compound of formula (I) wherein A is -O- and R 3 is H: wherein P is as hereinbefore defined; and thereafter, either prior to or after deprotection, optionally converting the compound of formula (IB) so prepared to another compound of formula (I) or salt thereof.
  • a reducing agent such as a metal hydride (e.g . Lithium borohydride)
  • Conversion of the -(CH 2 ) n OH group of formula (IB) may take place by methods known to those skilled in the art. For example, standard methods may be used to prepare compounds of formula (I) wherein A is -OCONR a or -AR 3 is OR 3 wherein R 3 is not H from the corresponding compound of formula (IB).
  • a method to prepare compounds of formula (IIA) where q is 1, comprises reacting the corresponding compound of formula (IB) wherein n is 1 with methanesulphonyl chloride in the presence of triethylamine to produce the corresponding methanesulphonate of formula (XII): wherein n is 1, which can thereafter be reacted with an alkali metal cyanide to produce the compound of formula (IIA) wherein q is 1.
  • the methanesulphonate of formula (XII) wherein n is 1 or 2 may be reacted with a compound of formula R 3 A 2 M, wherein A 2 is O or S and M is a metal, such as sodium, to produce (after deprotection) the corresponding compound of formula (I) wherein A is O or S.
  • may then be oxidised (as described below for the oxidation of the intermediate of formula (VI)) to the corresponding sulphone (wherein A SO 2 ).
  • the unprotected methanesulphonate intermediate may be reacted with
  • a suitable method to prepare compounds of formula (I) wherein A is -NH but R 3 is other than H is by reductive amination, which comprises reaction of the corresponding compound of formula (IA) with a suitable aldehyde or ketone precursor for the group R 3 in the presence of a suitable reducing agent such as sodium triacetoxyborohydride, optionally in the presence of acetic acid, and in an inert solvent, such as THF or dichloromethane.
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • the compound of formula (IIA) wherein q is 0 ( i.e. n is 1) may be prepared by reaction of the corresponding compound of formula (III): with a protected ester of formula (IV): wherein P 1 is a protecting group, preferably -C(O)Ph.
  • Suitable de-protection, such as de-esterification, methods include (a) enzymatic de-esterification with an esterase; and (b) chemical de-esterification with a base, such as sodium methoxide, sodium carbonate or ammonia, in a suitable solvent, e.g. methanol or ethanol.
  • a suitable solvent e.g. methanol or ethanol.
  • the compound of formula (III) may be prepared from the corresponding protected compound of formula (V): wherein P 2 is a protecting group, such as tetrahydropyranyl (THP) and R e is alkyl with a suitable cyanide derivative, such as an alkali metal cyanide such as KCN, followed by deprotection, such as with a mineral acid, e.g . aqueous HCl, in an alcoholic solvent, e.g . ethanol.
  • P 2 is a protecting group, such as tetrahydropyranyl (THP) and R e is alkyl with a suitable cyanide derivative, such as an alkali metal cyanide such as KCN, followed by deprotection, such as with a mineral acid, e.g . aqueous HCl, in an alcoholic solvent, e.g . ethanol.
  • THP tetrahydropyranyl
  • R e is alkyl with a suitable cyanide derivative
  • the compound of formula (V) may itself be prepared from the corresponding compound of formula (VI): wherein P 2 and R e are as defined in formula (V), by reaction with an oxidising agent, such as potassium peroxymonosulphate (OXONE (trade mark)).
  • an oxidising agent such as potassium peroxymonosulphate (OXONE (trade mark)
  • the compound of formula (VI) may itself be prepared from the corresponding halide of formula (VII): wherein P 2 is as defined in formula (VI), and X 1 is halo, preferably chloro, by reaction with a corresponding thioalkoxide, such as sodium thiomethoxide.
  • the compound of formula (VII) may be prepared from the protected starting material of formula (VIII): wherein P 2 and X 1 are as previously defined, and X 2 is a leaving group, such as halo, preferably chloro, by reaction with an amine of formula R 2 NH 2 .
  • the protected starting material of formula (VIII) may itself be prepared by standard protecting methods from a 2,6-dihalopurine, such as by reaction with 2,3-dihydropyran in the presence of catalytic 4-toluenesulphonic acid.
  • the compound of formula (IV) may be prepared from the corresponding ether of formula (IX): wherein P 1 is as defined in formula (IV), by standard methods, such as by reaction with acetic acid/acetic anhydride in the presence of sulphuric acid.
  • the protected ether of formula (IX) may itself be prepared from the compound of formula (X): by reaction with an acid, e.g . aqueous HCl, in a polar solvent, e.g . methanol, followed by protection of the reactive hydroxyl groups, as hereinbefore described, such as by using benzoyl chloride in the presence of an acid acceptor, e.g . pyridine.
  • an acid e.g aqueous HCl
  • a polar solvent e.g . methanol
  • the compound of formula (X) may be prepared from the corresponding alcohol of formula (XI): by standard methods, such as by the formation of an alkoxide ion by reaction with sodium hydride, and then reaction with a compound of formula R 1 -X 3 wherein X 3 is a leaving group such as halo, preferably iodo.
  • the compound of formula (XI) is obtainable from D-ribose as described in J. Het. Chem., 13 , 485 (1966).
  • All the compounds of the formula (I) may be prepared by deprotection of the corresponding compound (XIII) wherein the 3- and 4- hydroxy groups on the pendant tetrahydrofuran ring are suitably protected, e.g. by t-butyldimethylsilyl groups, under suitable conditions, e.g. using tetra-n-butylammmonium fluoride in THF.
  • suitable protecting groups and deprotection conditions are well-known to the skilled person such as from the Greene reference mentioned above.
  • Compounds of the formula (I) wherein A is C(O)NR a may be prepared from the corresponding carboxylic acid (e.g. a compound of the formula (IIB)) by condensation with a suitable amine of the formula NHR 3 R a .
  • suitable condensation conditions include using N,N-dicyclohexylcarbodiimide, 1H-1,2,3-benzotriazol-1-ol monohydrate, diisopropylethylamine and dichloromethane.
  • a pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the anti-inflammatory properties of the compounds of the formula (I) are demonstrated by their ability to inhibit neutrophil function which indicates A2a receptor agonist activity. This is evaluated by determining the compound profile in an assay where superoxide production was measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation through Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis with ice-cold distilled water. Superoxide production from the neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B.
  • Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might suppress superoxide production.
  • the effect of the compound on the fMLP-induced response was monitored colorometrically from the reduction of cytochrome C within the assay buffer.
  • the potency of the compounds was assessed by the concentration giving 50% inhibition (IC 50 ) compared to the control response to fMLP.
  • the compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed- or controlled-release applications.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably com, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably com, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol.
  • the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.
  • the compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the daily dosage level of the compounds of the formula (I) will usually be from 0.01 to 100 mg/kg, body weight of the subject to be treated, preferably from 0.1 to 100 mg/kg (in single or divided doses).
  • tablets or capsules of the compound of the formula (I) may contain from 5 to 500 mg of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • the compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroe
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff" contains from 20 to 4000 ⁇ g of a compound of the formula (I) for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 20 ⁇ g to 20mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment, gel, suspension, dusting powder, spray or drug-incorporated dressing (e.g. a tulle dressing, a white soft paraffin or polyethylene glycol impregnated gauze dressing, or a hydrogel, hydrocolloid, alginate or film dressing).
  • the compounds of the formula (I) may also be transdermally administered, for example, by the use of a skin patch.
  • the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • They can also be formulated as a hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers.
  • TBDMS tert-butyldimethylsilyl and psi means pounds per square inch.
  • thin layer chromatography refers to silica gel TLC using silica gel 60 F 254 plates, R f is the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.
  • the solvent was removed under reduced pressure and methanol (20ml), saturated with ammonia gas, added.
  • the resultant mixture was stirred at room temperature for 2hr, treated with 2 molar aqueous sodium hydroxide (10ml) and then left standing at room temperature for 24hr.
  • the methanol was removed under reduced pressure and the aqueous layer extracted with dichloromethane (x3).
  • the combined organic layers were washed with water (x2), dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure.
  • the residue was dissolved in 1,4-dioxan (6ml), 0.88 aqueous ammonia solution (8ml) added and the mixture stirred at room temperature for 10 days.
  • the 1,4-dioxan was removed under reduced pressure and the aqueous layer extracted with dichloromethane (x3).
  • the title compound was prepared by a similar method to example 3 from (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110mg, 0.22mmol), 1-propanesulphonyl chloride (28mg, 0.19mmol) and triethylamine (0.1ml, 0.72mmol).
  • EXAMPLE 17 Cis -(2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-diphenylethyl)amino]-2- ⁇ [(4-isopropylcyclohexyl)amino]methyl ⁇ -9 H -purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol and trans -(2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-diphenylethyl)amino]-2- ⁇ [(4-isopropylcyclohexyl)amino]methyl ⁇ -9 H- purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol
  • the resulting solution was cooled to room temperature and; with stirring, treated with a solution of 4-isopropylcyclohexanone (85mg, 0.61 mmol) and acetic acid (44mg) in dry tetrahydrofuran (5ml), followed by addition of solid sodium triacetoxyborohydride (194mg, 0.91 mmol).
  • the resulting mixture was then stirred at room temperature for 18hr before removal of the solvent under reduced pressure and partitioning of the residue between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic phase was separated and the solvent removed under reduced pressure.
  • EXAMPLE 19 N-( ⁇ 9-[2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl ⁇ methyl)-5-methyl-2-(2,2,2-trifiuoroacetyl)-1,2,3,4-tetrahydro-8-isoquinolinesulfonamide.
  • EXAMPLE 20 N-( ⁇ 9-[2R,3R,4S,5R ⁇ -3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl ⁇ amino]-9H-purin-2-yl ⁇ )-5-methyl-1,2,3,4-tetrahydro-8-isoquinolinesulfonamide.
  • EXAMPLE 21 N -( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)-4-[1-(2,2,2-trifluoroacetyl)-4-piperidinyl]benzenesulfonamide.
  • EXAMPLE 23 N -( ⁇ 9-[(2 R, 3 R, 4 S, 5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)-2-methoxy-1-ethanesulfonamide.
  • EXAMPLE 24 N -( ⁇ 9-[(2 R, 3 R, 4 S, 5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)(tetrahydro-2 H -pyran-4-yl)methanesulfonamide.
  • EXAMPLE 25 N -( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino] - 9 H- purin-2-yl ⁇ methyl)-2-propanesulfonamide.
  • EXAMPLE 26 N -( ⁇ 9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)-2,2-dimethyl-1-propanesulfonamide.
  • EXAMPLE 27 N-( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2 furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)(phenyl)methanesulfonamide.
  • EXAMPLE 28 N -( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)-1-butanesulfonamide.
  • EXAMPLE 29 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2- ⁇ [(4-Chlorobenzyl)amino]methyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 32 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ [(4-isopropoxybenzyl)amino]methyl ⁇ -9 H -purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 33 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2- ⁇ [(3,4-Dimethoxybenzyl)amino]methyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 34 (2 R ,3 R ,4 S ,5 R )-2-[6-[(2,2-Diphenylethyl)amino]-2-( ⁇ [2-(methoxymethyl)benzyl]amino ⁇ methyl)-9 H -purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 35 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-( ⁇ [4-(Aminomethyl)benzyl]amino ⁇ methyl)-6-[(2,2-diphenylethyl)amino]-9 H- purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • Example 36 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2- ⁇ 2-[(Cyclohexylmethyl)amino]ethyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • Example 37 N -(2- ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino] - 9 H- purin-2-yl ⁇ ethyl)methanesulfonamide.
  • Methanesulfonyl chloride (27mg, 0.22mmol) was added to a stirred solution of (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (120mg, 0.23mmol) (Example 11) and triethylamine (0.1 ml, 0.72mmol) in dichloromethane (10ml). The reaction mixture was stirred at room temperature for 2hr when the solvent was removed under reduced pressure.
  • Example 40 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-( ⁇ [trans-4-(Benzylamino)cyclohexyl]amino ⁇ methyl)-6-[(2,2-diphenylethyl)amino]-9 H- purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • Example 41 2-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]-N,N-diisopropylacetamide
  • the title compound was prepared by a similar method to example 40 using ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl)methyl methanesulfonate (preparation 25) (374mg, 0.66mmol), 2-amino- N,N -diisopropylacetamide (520mg, 3.3mmol) (preparation 22) and N -ethyl- N -isopropyl-2-propanamine (170mg, 1.32mmol).
  • the compound was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : ammonia (95 : 5 : 0.5) increasing in polarity to (90 : 10 : 1). The solvent was removed under reduced pressure to give a residue which was triturated with diethyl ether to give the title compound (47 mg) as a solid. MS: 632 (MH + ).
  • EXAMPLE 42 4- ⁇ [( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]methyl ⁇ benzonitrile.
  • EXAMPLE 43 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ [2- ⁇ 1-piperidinyl)ethoxy]methyl ⁇ -9 H -purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • the title compound was prepared by a similar method to example 38 using N- (9-[ ⁇ 2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ [2-(1-piperidinyl)ethoxy]methyl ⁇ -9 H- purin-6-yl)- N -(2,2-diphenylethyl)amine (100mg, 0.12mmol) (preparation 29), and a 1 M solution of tetra- n -butylammonium fluoride in tetrahydrofuran (0.5ml, 0.5mmol).
  • EXAMPLE 44 3-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]- N , N -dimethylpropanamide.
  • N , N -dimethylacrylamide (10mg, 0.1 mmol) was added and the reaction mixture heated to 50°C for a further 24hr. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane : methanol : ammonia (94 : 4 : 0.2) increasing in polarity to (93 : 7 : 0.3) to give the title compound (100mg) as a foam. MS: 590 (MH + ).
  • EXAMPLE 45 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 6-[(2,2-Diphenylethyl)amino]-2-[(phenylsulfanyl)methyl]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 46 (2 R ,3 R ,4 S ,5 R )-2-[6-[(2,2-Diphenylethyl)amino]-2-( ⁇ [2-(1-piperidinyl)ethyl]amino ⁇ methyl)-9 H -purin-9yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 47 2- ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ -1-(4-isopropyl-1-piperidinyl)-1-ethanone.
  • the reaction mixture was stirred for 24hr at room temperature.
  • the solvent was then removed under reduced pressure, then the residue treated with ethyl acetate and the mixture filtered.
  • the solid was washed with ethyl acetate and the combined ethyl acetate filtrates washed with saturated aqueous sodium hydrogen carbonate solution, brine and dried with anhydrous magnesium sulfate.
  • the solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent system of dichloromethane : methanol : ammonia (95 : 5 : 0.5) to give some pure and some impure material.
  • EXAMPLE 48 (2 R ,3 R ,4 S ,5 R )-2-(2- ⁇ [2-(Dimethylamino)ethoxy]methyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • reaction mixture was agitated and heated to 60°C for 12hr. More 2,6-dimethyl-3-pyridinylamine (22mg, 0.17mmol) and triethylamine (0.036ml, 0.26mmol) were added and heating and agitation continued for a further 24hr. The reaction mixture was then washed with water and the organic phase separated and dried with anhydrous magnesium sulfate.
  • EXAMPLE 50 N - ⁇ 4-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino)-9 H- purin-2-yl ⁇ methyl)amino]trans-cyclohexyl ⁇ methanesulfonamide.
  • N -(trans-4-Aminocyclohexyl)methanesulfonamide (183mg, 0.8mmol) (preparation 33) was added to a stirred solution of ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl)methyl methanesulfonate (230mg, 0.4mmol) (preparation 25) and N -ethyl- N -isopropyl-2-propanamine (210mg, 1.6mmol) in ethanol (3ml) and dichloromethane (12ml).
  • EXAMPLE 51 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ 2-[(2-methoxyethyl)amino]ethyl ⁇ -9 H -purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • the title compound was prepared by a similar method to example 38 using N- (2- ⁇ 9-[(2 R, 3 R, 4 R, 5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ ethyl)- N -(2-methoxyethyl)amine (150 mg, 0.19mmol) (preparation 34) and a 1 molar solution of tetra- n -butylammonium fluoride in tetrahydrofuran (0.5ml, 0.5mmol).
  • EXAMPLE 53 tert -Butyl 4-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]-1-piperidinecarboxylate
  • EXAMPLE 54 (2 R ,3 R ,4 S ,5 R )-2-[6-[(2,2-Diphenylethyl)amino]-2-( ⁇ [(1-(2-pyridinyl)-4-piperidinyl]amino ⁇ methyl)-9 H -purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 55 tert -Butyl ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methylcarbamate.
  • EXAMPLE 56 4-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]tetrahydro-1 ⁇ 6 -thiopyran-1,1(2 H )-dione.
  • the title compound was prepared by a similar method to example 6 using (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(aminomethyl)-6-[(2,2-diphenylethyl)amino ⁇ -9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (305mg, 0.60mmol) (example 1), tetrahydro-1 ⁇ 6 -thiopyran-1,1,4-trione (88mg, 0.60mmol), sodium triacetoxyborohydride (200mg, 0.90mmol) and acetic acid (43mg, 0.72mmol).
  • EXAMPLE 57 ⁇ 4-[( ⁇ 9-[(2 R, 3 R, 4 S, 5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]-1-piperidinyl ⁇ (phenyl)methanone
  • the title compound was prepared by a similar method to example 6 using (2 R, 3 R, 4 S, 5 R )-2-(2-(aminomethyl)-6-[(2,2-diphenylethyl)amino ⁇ -9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (310mg, 0.63mmol) (example 1), 1-benzoyl-4-piperidinone (128mg, 0.63mmol), sodium triacetoxyborohydride (200mg, 0.90mmol) and acetic acid (45mg, 0.74mmol).
  • the title compound was prepared by a similar method to example 3 using (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)-tetrahydro-3,4-furandiol (example 11) (200mg, 0.40mmol), phenylsulfonyl chloride (70mg, 0.40mmol) and triethylamine (0.15ml, 1.08mmol).
  • EXAMPLE 59 N -( tert -Butyl)-3-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]propanamide.
  • EXAMPLE 60 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(2-[(1-Benzhydryl-3-azetidinyl)amino]ethyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • the title compound was prepared by a similar method to example 38 using 2- ⁇ 2-[(1-benzhydryl-3-azetidinyl)amino]ethyl ⁇ -9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]- N -(2,2-diphenylethyl)-9 H -purin-6-amine (130mg, 0.14mmol) (preparation 38) and a 1 molar solution of tetra- n -butylammonium fluoride in tetrahydrofuran (0.4ml, 0.4mmol).
  • the title compound was prepared by a similar method to example 5 using (2 R ,3 R ,4 S ,5 R )-2-(2-(aminomethyl)-6-[(2,2-diphenylethyl)amino ⁇ -9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (320mg, 0.63mmol) (example 1), 2-methoxyacetaldehyde (53mg, 0.63mmol) and sodium triacetoxyborohydride (210mg, 0.95mmol) in tetrahydrofuran (22ml).
  • EXAMPLE 62 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 6-[(2,2-Diphenylethyl)amino]-2-[(isobutylamino)methyl]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol and EXAMPLE 63: (2 R ,3 R ,4 S ,5 R )-2-(2-[(Diisobutylamino)methyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 64 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ [(1-methyl-4-piperidinyl)amino]methyl ⁇ -9 H -purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol.
  • EXAMPLE 65 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ [(4-methoxycyclohexyl)amino]methyl ⁇ -9 H- purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4 furandiol
  • EXAMPLE 66 (2 R, 3 R, 4 S, 5 R )-2- ⁇ 2- ⁇ [4,4-Dimethylcyclohexyl)amino]methyl ⁇ -6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • the title compound was prepared by a similar method to example 6 using (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(aminomethyl)-6-[(2,2-diphenylethyl)amino ⁇ -9 H -purin-9-y) ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (330mg, 0.67mmol) (example 1), sodium triacetoxyborohydride (214mg, 1.01 mmol), 4,4-dimethylcyclohexanone (85mg, 0.67mmol) and acetic acid (48mg, 0.80mmol) in tetrahydrofuran (30ml).
  • the title compound was prepared by a similar method to example 38 using the compound of preparation 40 (190mg, 0.21mmol) and tetra-n-butyl ammonium fluoride (0.6ml of a 1 molar solution in tetrahydrofuran, 0.6mmol) in tetrahydrofuran (3ml).
  • the product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane : methanol (97 : 3) increasing in polarity to dichloromethane : methanol : ammonia (95 : 5 : 0.5) to give the title compound (79mg) as a foam.
  • Phenylsulfonylchloride (57mg, 0.33mmol) was added to a stirred solution of (2 R ,3 R ,4 S ,5 R )-2-[2-(aminomethyl)-6-(phenethylamino)-9 H -purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol (150mg, 0.36mmol) (preparation 48) and triethylamine (110mg, 1.08mmol) in tetrahydrofuran (24ml). The reaction mixture was stirred for 30min at room temperature and then the solvent was removed under reduced pressure.
  • EXAMPLE 70 (2 R, 3 R, 4 S, 5 R )-2- ⁇ 2-[2-(Benzylamino)ethyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol
  • the title compound was prepared by a similar method to example 38 using N- benzyl- N -(2- ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ ethyl)amine (360 mg, 0.44mmol) (preparation 39) and a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran (0.92ml, 0.92mmol).
  • EXAMPLE 71 6-[( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)amino]nicotinonitrile
  • 6-Chloronicotinonitrile (78mg, 0.56mmol) was added to a stirred solution of (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-(aminomethyl)-6-[(2,2-diphenylethyl)amino ⁇ -9 H -purin-9-yl ⁇ -5-(methoxymethyl)tetrahydro-3,4-furandiol (250mg, 0.51 mmol) (example 1) and triethylamine (57mg, 0.56mmol) in N -methyl-2-pyrrolidinone (10ml). The reaction mixture was heated at 120°C for 24hr. The reaction mixture was then partitioned between water and ethyl acetate.
  • EXAMPLE 72 (2 R ,3 R ,4 S ,5 R )-2-(6-[(2,2-Diphenylethyl)amino]-2- ⁇ [(1-methyl-4-piperidinyl)oxy]methyl ⁇ -9 H -purin-9-yl)-5-(methoxymethyl)tetrahydro-3,4-furandiol
  • reaction mixture was stirred at room temperature for 1 hr and then more 1 molar solution of tetrabutylammonium fluoride (0.5ml, 0.5mmol) was added.
  • the reaction mixture was stirred for another hour and then partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate phase was separated, washed with brine and dried with anhydrous sodium sulfate.
  • Example 74 Potassium N -( ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl)-2-methyl-1-propanesulfamate.
  • EXAMPLE 76 (2 R ,3 R ,4 S ,5 R )-2- ⁇ 2-[(Benzylsulfanyl)methyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -5- ⁇ methoxymethyl)tetrahydro-3,4-furandiol.
  • PREPARATION 1 (3a R ,4 R ,6 R ,6a R )-4-Methoxy-6-(methoxymethyl)-2,2-dimethyltetrahydrofuro[3,4- d ][1,3]dioxole
  • PREPARATION 2 (2 R ,3 R ,4 S ,5 R )-2-Methoxy-5-(methoxymethyl)tetrahydro-3,4-furandiol and (2 S ,3 R ,4 S ,5 R )-2-methoxy-5-(methoxymethyl)tetrahydro-3,4-furandiol
  • PREPARATION 3 (2 R ,3 R ,4 R ,5 R )-4-(Benzoyloxy)-5-methoxy-2-(methoxymethyl)tetrahydro-3 furanyl benzoate and (2 R ,3 R ,4 R ,5 S )-4-(benzoyloxy)-5-methoxy-2-(methoxymethyl)tetrahydro-3-furanyl benzoate
  • PREPARATION 4 (2 R, 3 R, 4 R, 5 S )-5-(Acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate and (2 R ,3 R ,4 R ,5 R )-5-(acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate
  • the resultant mixture was stirred at room temperature for 24hr.
  • the reaction mixture was then diluted with water (1000ml), solid sodium hydrogen carbonate (80g) added portion wise to neutralise the solution (pH 7) and the mixture stirred for a further 2hr.
  • Dichloromethane (500ml) and water (500ml) were added to the reaction mixture and the layers were separated.
  • the aqueous layer was then extracted with dichloromethane, and the combined organic layers washed with brine, dried with anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure to afford the title compound as an oil and as a mixture of anomers (57.5g).
  • PREPARATION 7 N -(2,2-Diphenylethyl)-2-(methylsulfanyl)-9-tetrahydro-2 H -pyran-2-yl-9 H -purin-6-amine
  • PREPARATION 8 N -(2,2-Diphenylethyl)-2-(methylsulfonyl)-9-tetrahydro-2 H -pyran-2yl-9 H -purin-6-amine
  • PREPARATION 11 (2 R ,3 R ,4 R ,5 R )-4-(benzoyloxy)-5- ⁇ 2-cyano-6-[(2,2-diphenylethyl)amino]-9 H -purin-9-yl ⁇ -2-(methoxymethyl)tetrahydro-3-furanyl benzoate
  • PREPARATION 12 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purine-2-carbonitrile
  • PREPARATION 14 Methyl 9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purine-2-carboxylate
  • PREPARATION 15 ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ methanol
  • PREPARATION 16 ⁇ 9-[(2 R, 3 R, 4 R, 5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ methyl methanesulfonate
  • Methanesulfonyl chloride (0.6ml, 7.7mmol) was slowly added to a stirred solution of ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H purin-2-yl ⁇ methanol (4.22g, 5.87mmol) (preparation 15) and triethylamine (1.2ml, 8.62mmol) in dichloromethane (50ml) and the mixture stirred at room temperature for 30 minutes.
  • PREPARATION 17 2- ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ acetonitrile
  • PREPARATION 18 N - ⁇ 2-(2-Aminoethyl)-9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-9 H -purin-6-yl ⁇ - N -(2,2-diphenylethyl)amine
  • PREPARATION 19 N -(2- ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino)-9 H -purin-2-yl)ethyl)- N -(1-ethylpropyl)amine
  • PREPARATION 21 Tetrahydro-2 H -pyran-4-ylmethanesulfonyl chloride.
  • PREPARATION 22 2-Amino- N , N -diisopropylacetamide.
  • Trimethylacetylchloride (1.8g, 15mmol) was added to a stirred solution of 2-[( tert -butoxycarbonyl)amino)acetic acid (2.6g, 15mmol) and triethylamine (5ml, 36mmol) in dichloromethane (30ml) at 0°C.
  • the reaction mixture was stirred for 10min and then N -ethyl- N -isopropyl-2-propanamine (2.5ml, 18mmol) was added.
  • the reaction was allowed to warm to room temperature and stirred for 24hr.
  • the solvent was removed under reduced pressure and the residue taken up into a mixture of methanol (30ml) and water (5ml).
  • PREPARATION 23 N -(9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ 2-[(cyclohexylmethyl)amino]ethyl ⁇ -9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine
  • PREPARATION 24 2-[(Benzyloxy)methyl)-9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]- N -(2,2-diphenylethyl)-9 H -purin-6-amine
  • PREPARATION 25 ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ methyl methanesulfonate.
  • the title compound was prepared by a similar method to example 5 from tert- butyl trans-4-aminocyclohexylcarbamate (1.0g, 4.7mmol) (J. Org. Chem. 8811, 61 , 1996), benzaldehyde (530mg, 5mmol) and sodium triacetoxyborohydride (2.0g, 9.4mmol).
  • the product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane : methanol : ammonia (95 : 5 : 0.5) to give the title compound (0.73g) as a solid.
  • PREPARATION 28 4-(Bromomethyl)tetrahydro-2 H -pyran.
  • Triphenylphosphine (3.93g, 15mmol) was added to a stirred ice-cold solution of tetrahydro-2 H -pyran-4-ylmethanol (1.16g, 10mmol) (WO 96/07410) and carbon tetrabromide (4.97g, 15mmol) in dichloromethane (50ml). The reaction temperature was allowed to rise to room temperature and then the reaction mixture was stirred at room temperature for 24hr.
  • PREPARATION 29 N -(9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ [2-(1-piperidinyl)ethoxy]methyl ⁇ -9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine
  • PREPARATION 30 2- ⁇ 9-[(2 R ,3 R ,4 S ,5 R ),3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2 furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ acetonitrile
  • PREPARATION 31 2,2,2-Trifluoro-1-(4-phenyl-1-piperidinyl)-1-ethanone.
  • Trifluoroacetic anhydride (32.6g, 0.155mol) was slowly added to a stirred solution of 4-phenylpiperidine (25g, 0.155mol) and N-methylmorpholine (15.6g, 0.155mol) in dichloromethane (250ml) at between -10°C and -15°C. The reaction mixture was allowed to warm to room temperature and then stirred for a further 24hr.
  • PREPARATION 32 tert -Butyl trans-4-[(methylsulfonyl)amino]cyclohexylcarbamate.
  • Methanesulfonyl chloride (0.56g, 4.7mmol) was added to a stirred solution of tert -butyl trans-4-aminocyclohexylcarbamate (J. Org. Chem. 8811, 61, 1996) (1.0g, 4.7mmol) and N -ethyl- N -isopropyl-2-propanamine (0.67g, 0.52mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 30min at room temperature and then partitioned between ethyl acetate (300ml) and water (100ml).
  • PREPARATION 34 N -(2- ⁇ 9-1(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ ethyl)- N -(2-methoxyethyl)amine
  • the title compound was prepared by a similar method to preparation 23 from the compound of preparation 18 (250mg, 0.34mmol), sodium triacetoxyborohydride (120mg, 0.56mmol) and 2-methoxyacetaldehyde (28mg, 0.33mmol).
  • the compound was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol : ammonia (95 : 5 : 0.5) to give the title compound (155mg) as a foam.
  • PREPARATION 35 N-(9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ [cyclohexyl(methyl)amino]methyl ⁇ -9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine.
  • N -Cyclohexyl- N -methylamine (30mg, 0.27mmol) was added to a stirred solution of ⁇ 9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ methyl methanesulfonate (150mg, 0.19mmol) (preparation 16) and potassium carbonate (60mg, 0.44mmol) in acetonitrile (10ml).
  • PREPARATION 38 2- ⁇ 2-[(1-Benzhydryl-3-azetidinyl)amino ]ethyl ⁇ -9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]- N -(2,2-diphenylethyl)-9 H -purin-6-amine
  • PREPARATION 39 N- Benzyl -N- (2- ⁇ 9-[(2 R, 3 R, 4 R, 5 R )-3,4-bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H -purin-2-yl ⁇ ethyl)amine.
  • the title compound was prepared by a similar method to example 5 from N - ⁇ 2-(2-aminoethyl)-9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-9 H -purin-6-yl ⁇ - N -(2,2-diphenylethyl)amine (430mg, 0.58mmol) (preparation 18), benzaldehyde (65mg, 0.61 mmol) and sodium triacetoxyborohydride (270mg, 1.27mmol) in tetrahydrofuran (15ml).
  • PREPARATION 40 N -(9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ 2-[(cyclopropylmethyl)amino]ethyl ⁇ -9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine
  • the title compound was prepared by a similar method to example 5 from N - ⁇ 2-(2-aminoethyl)-9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine (430mg, 0.58mmol) (preparation 18), cyclopropanecarbaldehyde (45mg, 0.64mmol) and sodium triacetoxyborohydride (270mg, 1.27mmol) in tetrahydrofuran (10ml).
  • PREPARATION 41 2-Chloro- N -phenethyl-9-tetrahydro-2 H -pyran-2-yl-9 H- purin-6-amine.
  • Phenethylamine (7.0g, 58.4mmol) was added to a stirred solution of 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (14.5g, 53.1 mmol) (preparation 5) and triethylamine (21g, 212.5mmol) in acetonitrile (200ml). The reaction mixture was stirred for 3hr at room temperature and then more phenethylamine (1 g, 8.3mmol) was added. The reaction mixture was stirred for a further 1 hr and then the solvent was removed under reduced pressure to give a residue which was partitioned between diethyl ether (500ml) and water (250ml).
  • PREPARATION 42 2-(Methylsulfanyl)- N -phenethyl-9-tetrahydro-2 H -pyran-2-yl-9 H -purin-6-amine
  • the title compound was prepared by a similar method to preparation 7 from 2-chloro- N -phenethyl-9-tetrahydro-2 H -pyran-2-yl-9 H -purin-6-amine (17.5g, 49mmol) (preparation 41) and sodium thiomethoxide (7.2g, 75mmol). This gave the title compound (16.7g) as a white solid.
  • PREPARATION 43 2-(Methylsulfonyl)- N -phenethyl-9-tetrahydro-2 H -pyran-2-yl-9 H -purin-6-amine
  • PREPARATION 46 (2 R ,3 R ,4 R ,5 R )-4-(Benzoyloxy)-5-[2-cyano-6-(phenethylamino)-9 H -purin-9 yl]-2-(methoxymethyl)tetrahydro-3-furanyl benzoate
  • the title compound was prepared by a similar method to preparation 11 using 6-(phenethylamino)-9 H -purine-2-carbonitrile (3.8g, 11.2mmol) (preparation 45), (2 R, 3 R, 4 R, 5 S )-5-(acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate and (2 R, 3 R, 4 R, 5 R )-5-(acetyloxy)-4-(benzoyloxy)-2-(methoxymethyl)tetrahydro-3-furanyl benzoate (preparation 4) (6g, 14.5mmol), ammonium sulfate (200mg, 1.2mmol), 1,1,1,3,3,3-hexamethyldisilazane (150ml), bromotrimethylsilane (8ml, 177mmol), acetonitrile (80ml), dichloromethane (80ml) and bismuth tribromid
  • PREPARATION 47 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-(phenethylamino)-9 H -purine-2-carbonitrile
  • PREPARATION 48 (2 R ,3 R ,4 S ,5 R )-2-[2-(Aminomethyl)-6-(phenethylamino)-9 H -purin-9-yl]-5-(methoxymethyl)tetrahydro-3,4-furandiol
  • PREPARATION 49 N -(9-[(2 R ,3 R ,4 R ,5 R )-3,4-Bis ⁇ [ tert- butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-2- ⁇ [(1-methyl-4-piperidinyl)oxy]methyl ⁇ -9 H -purin-6-yl)- N -(2,2-diphenylethyl)amine
  • PREPARATION 50 2-( ⁇ [Amino(imino)methyl]sulfanyl ⁇ methyl)-9-[(2 R ,3 R ,4 R ,5 R )-3,4-bis ⁇ [ tert -butyl(dimethyl)silyl]oxy ⁇ -5-(methoxymethyl)tetrahydro-2-furanyl]-6-1(2,2-diphenylethyl)amino]-9H-purine
  • PREPARATION 51 2- ⁇ 9-[(2 R ,3 R ,4 S ,5 R )-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9 H- purin-2-yl ⁇ acetic acid
  • the aqueous phase was acidified to pH ⁇ 7 with a 1 molar aqueous citric acid solution and then extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried with anhydrous magnesium sulfate. The residue, after removal of the solvent under reduced pressure, was dissolved into diethyl ether and the solvent removed again twice under reduced pressure to give the title compound (1.25g) as a foam. MS: 518 (M-H + ).

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Claims (32)

  1. Verbindung der Formel (I):
    Figure imgb0151
     worin
    R1 Alkyl oder Cyclopropylmethyl ist;
    R2 Phenylalkylen oder Naphthylalkylen ist, wobei die Alkylenkette gegebenenfalls weiter mit Phenyl oder Naphthyl substituiert ist, wobei jedes Phenyl oder Naphthyl gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus Alkyl, Alkoxy, Halogen und Cyano, substituiert ist;
    n 1 oder 2 ist;
    A NRa, NRaC (O) , NRaC (O) NRa, NRaC(O)O, OC(O)NRa, C(O)NRa, NRaSO2, SO2NRa, O, S, oder SO2 ist;
    Ra H, Alkyl oder Benzyl ist, gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus Alkyl, Alkoxy, Halogen und Cyano, ring-substituiert,
    R3 eine Gruppe der Formel -(CH2)p-Rp-B ist;
    p 0, 1 oder 2 ist;
    Rp eine Bindung, Alkylen, Cycloalkylen, Phenylen oder Naphthylen ist, wobei das Cycloalkylen, Phenylen und Naphthylen gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus Alkyl, Alkoxy, Halogen und Alkoxyalkylen, substituiert sind;
    B
    (i) H, -NRbRb, RbRbN-Alkylen, -ORb, -COORb, -OCORb, -SO2Rb, -CN, -SO2NRbRb, -NRbCORb, -NRbSO2Rb oder -CONRbRb, in denen jedes Rb das gleiche oder verschieden ist und aus H, Alkyl, Phenyl und Benzyl ausgewählt ist, unter der Maßgabe, dass
    (a) wenn B -OCORb, -SO2Rb, -NRbCORb oder -NRbSO2Rb ist, das terminale Rb dann nicht H ist und
    (b) Rp eine Bindung ist, p 0 ist und B H ist, nur wenn A NRa, NRaC (O) NRa, OC(O)NRa, C (O) NRa, SO2NRa, O oder S ist,
    (ii) eine gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, oder
    (iii) N-verknüpftes Azetidinyl, Pyrrolidinyl, Piperidinyl, Piperazinyl oder Morpholinyl, jedes gegebenenfalls mit einem oder mehreren Alkylsubstituenten substituiert, mit der Maßgabe, dass -(CH2)p-Rp- nicht -CH2- ist, ist; und
    wenn A NRa, C(O)NRa, OC(O)NRa oder SO2NRa ist, können Ra und R3 zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, einen Azetidin-, Pyrrolidin-, Piperidin- oder Piperazin-Ring bilden, gegebenenfalls mit einem oder mehreren Alkylsubstituenten substituiert,
    oder ein pharmazeutisch annehmbares Salz oder Solvat davon.
  2. Verbindung nach Anspruch 1, worin
    R1 C1-C6-Alkyl oder Cyclopropylmethyl ist;
    R2 Phenyl-(C1-C6)-alkylen oder Naphthyl-(C1-C6)-alkylen ist, wobei die C1-C6-Alkylenkette gegebenenfalls weiter mit Phenyl oder Naphthyl substituiert ist, wobei jedes Phenyl oder Naphthyl gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus C1-C6-Alkyl, C1-C6-Alkoxy, Halogen und Cyano, substituiert ist;
    n 1 oder 2 ist;
    A NRa, NRaC(O), NRaC(O)NRa, NRaC(O)O, OC(O)NRa, C(O)NRa, NRaSO2, SO2NRa, O, S, oder SO2 ist;
    Ra H, C1-C6-Alkyl oder Benzyl ist, gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus C1-C6-Alkyl, C1-C6-Alkoxy, Halogen und Cyano, ring-substituiert,
    R3 eine Gruppe der Formel -(CH2)p-Rp-B ist;
    p 0, 1 oder 2 ist;
    Rp eine Bindung, C1-C6-Alkylen, C3-C7-Cycloalkylen, Phenylen oder Naphthylen ist, wobei das C3-C7-Cycloalkylen, Phenylen und Naphthylen gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus C1-C6-Alkyl, Cl-C6-Alkoxy, Halogen und C1-C6-Alkoxy-C1-C6-alkylen, substituiert sind;
    B
    (i) H, -NRbRb, RbRbN-(C1-C6)-Alkylen, -ORb, -COORb, -OCORb, -SO2Rb, -CN, -SO2NRbRb, -NRbCORb, -NRbSO2Rb oder -CONRbRb, in denen jedes Rb das gleiche oder verschieden ist und aus H, C1-C6-Alkyl, Phenyl und Benzyl ausgewählt ist, unter der Maßgabe, dass
    (a) wenn B -OCORb, -SO2Rb, -NRbCORb oder -NRbSO2Rb ist, das terminale Rb dann nicht H ist und
    (b) Rp eine Bindung ist, p 0 ist und B H ist, nur wenn A NRa, NRaC(O)NRa, OC(O)NRa, C(O)NRa, SO2NRa, O oder S ist,
    (ii) eine gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, oder
    (iii) N-verknüpftes Azetidinyl, Pyrrolidinyl, Piperidinyl, Piperazinyl oder Morpholinyl, jedes gegebenenfalls mit einem oder mehreren C1-C6-Alkylsubstituenten substituiert, mit der Maßgabe, dass -(CH2)p-Rp- nicht -CH2- ist, ist; und
    wenn A NRa, C(O)NRa, OC(O)NRa oder SO2NRa ist, können Ra und R3 zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, einen Azetidin-, Pyrrolidin-, Piperidin- oder Piperazin-Ring bilden, gegebenenfalls mit einem oder mehreren C1-C6-Alkyl-substituenten substituiert.
  3. Verbindung nach Anspruch 1 oder 2, worin in der Definition von B die gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, 4 bis 12 Ringatome hat, jedes unabhängig ausgewählt aus C, N, O und S.
  4. Verbindung nach Anspruch 3, worin in der Definition von B die gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, 4 bis 10 Ringatome hat, jedes unabhängig ausgewählt aus C, N, O und S.
  5. Verbindung nach Anspruch 3 oder 4, worin in der Definition von B die gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, Ringatome hat, die ausgewählt sind aus 1 bis 4 N-Atomen, 1 oder 2 O- und 1 oder 2 S-Atomen, wobei die verbleibenden Ringatome C-Atome sind.
  6. Verbindung nach Anspruch 5, worin in der Definition von B die gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, 1 bis 4 Ring-N-Atome oder 1 bis 2 Ring-N-Atome und 1 O- oder 1 S-Ringatom oder 1 O- oder 1 S-Ringatom hat, wobei die verbleibenden Ringatome C-Atome sind.
  7. Verbindung nach einem der vorhergehenden Ansprüche, worin die vollständig oder teilweise gesättigte oder ungesättigte, mono- oder bicyclische, heterocyclische Gruppe, die durch ein Ringkohlenstoffatom an Rp gebunden ist, gegebenenfalls mit einem oder mehreren Substituenten, jeder unabhängig ausgewählt aus R5, -OR5, Halogen, Oxo, Hydroxy, Cyano, -COR5, -COOH, -COOR5, -CONH2, -CONHR5, -CONR5R5, Amino, -NHR5, -NR5R5, -SO2R5, -SO2NH2, -SO2NHR5, -SO2NR5R5, -NHCOR5, -NR5COR5, -NHSO2R5, -NR5SO2R5 und Pyridinyl, worin R5 C1-C6-Alkyl, C3-C7-Cycloalkyl, Phenyl oder Naphthyl ist, jedes gegebenenfalls substituiert mit C3-C7-Cycloalkyl, C1-C6-Alkoxy, Halogen, Phenyl, Naphthyl oder Benzylamino, subsituiert ist.
  8. Verbindung nach einem der vorhergehenden Ansprüche, worin R1 C1-C6-Alkyl ist.
  9. Verbindung nach Anspruch 8, worin R1 Methyl ist.
  10. Verbindung nach einem der vorhergehenden Ansprüche, worin R2 Phenyl-(C1-C6)-alkylen ist, wobei die C1-C6-Alkylenkette gegebenenfalls weiter mit Phenyl substituiert ist.
  11. Verbindung nach Anspruch 10, worin R2 2-Phenylethyl ist, wobei die Ethylkette gegebenenfalls weiter mit Phenyl substituiert ist.
  12. Verbindung nach Anspruch 11, worin R2 2-Phenylethyl oder 2,2-Diphenylethyl ist.
  13. Verbindung nach Anspruch 12, worin R2 2,2-Diphenylethyl ist.
  14. Verbindung nach einem der vorhergehenden Ansprüche, worin A NRa, NRaC (O), NRaC (O)O, C(O)NRa, NRaSO2, SO2NRa, O, S, oder SO2 ist.
  15. Verbindung nach Anspruch 14, worin A NRa oder NRaSO2 ist.
  16. Verbindung nach einem der vorhergehenden Ansprüche, worin Ra H, C1-C6-Alkyl oder Benzyl ist, gegebenenfalls mit einem oder mehreren C1-C6-Alkoxysubstituenten ring-substituiert.
  17. Verbindung nach Anspruch 16, worin Ra H, Methyl, 2-Methyl-prop-1-yl oder Methoxybenzyl ist.
  18. Verbindung nach Anspruch 17, worin Ra H, Methyl, 2-Methyl-prop-1-yl oder 2-Methoxybenzyl ist.
  19. Verbindung nach einem der Ansprüche 1 oder 2, worin R3 H,
    C1-C6-Alkyl, gegebenenfalls substituiert mit C3-C7-Cycloalkyl, C1-C6-Alkoxy, Amino, -NH(C1-C6-Alkyl), -N(C1-C6-Alkyl)2, -CONH2, -CONH(C1-C6-Alkyl), -CON(C1-C6-Alkyl)2, Phenyl (gegebenenfalls substituiert mit Halogen, C1-C6-Alkoxy, C1-C6-Alkoxy-(C1-C6)-alkylen, Amino-(C1-C6)-alkylen, Cyano oder Piperidinyl (gegebenenfalls substituiert mit C1-C6-Alkyl, Halogen-(C1-C6)-alkyl oder Halogen-(C1-C6)-alkanoyl)), Piperidinyl oder Tetrahydropyranyl, C3-C7-Cycloalkyl, gegebenenfalls substituiert mit C1-C6-Alkyl, C1-C6-Alkoxy, Benzylamino oder C1-C6-Alkansulfonamido, Phenyl, gegebenenfalls substituiert mit Halogen, C1-C6-Alkoxy, C1-C6-Alkoxy-(C1-C6)-alkylen, Amino-(C1-C6)-alkylen oder Piperidinyl (gegebenenfalls substituiert mit C1-C6-Alkyl, Halogen-(C1-C6)-alkyl oder Halogen-(C1-C6)-alkanoyl), oder Azetidinyl, Pyridinyl, Piperidinyl, Tetrahydrothiopyranyl oder 1,2,3,4-Tetrahydroisochinolinyl, jedes gegebenenfalls substituiert mit C1-C6-Alkyl, Benzhydryl, Halogen-(C1-C6)-alkanoyl, Oxo, Hydroxy, Cyano, C1-C6-Alkoxycarbonyl, Benzoyl oder Pyridinyl, ist.
  20. Verbindung nach Anspruch 19, worin R3 H, Methyl, n-Propyl, i-Propyl, 2-Methylprop-1-yl, 2,2-Dimethylprop-1-yl, n-Butyl, t-Butyl, Pentan-3-yl, Cyclopentyl, Cyclohexyl, 4-(Isopropyl)-cyclohexyl, Cyclopropylmethyl, Cyclohexylmethyl, 2-Methoxyethyl, 2-Dimethylaminoethyl, 2-(N,N-Dimethylcarbamoyl)ethyl, N,N-(Diisopropyl)carbamoylmethyl, 2-(N-t-Butylcarbamoyl)ethyl, Phenyl, Benzyl, 4-Chlorbenzyl, 2-Methoxybenzyl, 3,4-Dimethoxybenzyl, 4-(Isopropoxy)benzyl, 2-Methoxymethylbenzyl, 4-Aminomethylbenzyl, 4-Cyanobenzyl, 4,4-Dimethylcyclohexyl, 4-Methoxycyclohexyl, 4-Benzylaminocyclohexyl, 4-Methansulfonamidocyclohexyl, 2-Piperidinoethyl, 4-(Piperidin-4-yl)phenyl, 4-(1-Trifluoracetylpiperidin-4-yl)phenyl, 1-Benzhydrylazetidin-3-yl, 2,6-Dimethylpyridin-3-yl, 5-Cyanopyridin-2-yl, 1-Methylpiperidin-4-yl, 1-(Isopropyl)piperidin-4-yl, 1-t-Butoxycarbonylpiperidin-4-yl, 1-Benzoylpiperidin-4-yl, 1-(2-Pyridinyl)piperidin-4-yl, 1,1-Dioxotetrahydrothiopyran-4-yl, Tetrahydropyran-4-ylmethyl, 5-Methyl-1,2,3,4-tetrahydroisochinolin-8-yl oder 5-Methyl-2-trifluoracetyl-1,2,3,4-tetrahydroisochinolin-8-yl ist.
  21. Verbindung nach Anspruch 20, worin R3 Phenyl, Cyclohexyl, 5-Methyl-1,2,3,4-tetrahydroisochinolin-8-yl, 2-Methylprop-1-yl, i-Propyl, 2-Methoxybenzyl oder N,N-(Diisopropyl)carbamoylmethyl ist.
  22. Verbindung nach Anspruch 1 oder 2, worin -A-R3 Amino, Isopropylamino, Pentan-3-ylamino, 2-Methylprop-1-ylamino, Di-(2-methylprop-1-yl)amino, N-Cyclohexyl-N-methylamino, 2-Methoxyethylamino, 2-(N,N-Dimethylcarbamoyl)ethylamino, N,N-(Diisopropyl)carbamoylmethylamino, 2-(N-t-Butylcarbamoyl)-ethylamino, Cyclopentylamino, Cyclohexylamino, 4,4-Dimethylcyclohexylamino, 4-(Isopropyl)cyclohexylamino, 4-Methoxycyclohexylamino, cis-4-Methoxycyclohexylamino, trans-4-Methoxycyclohexylamino, 4-Benzylaminocyclohexylamino, trans-4-Benzylaminocyclohexylamino, 4-Methansulfonamidocyclohexylamino, trans-4-Methansulfonamidocyclohexylamino, Cyclopropylmethylamino, Cyclohexylmethylamino, Benzylamino, 4-Chlorbenzylamino, 2-Methoxybenzylamino, Di-(2-methoxybenzyl)amino, 4-(Isopropoxy)benzylamino, 3,4-Dimethoxybenzylamino, 2-Methoxymethylbenzylamino, 4-Aminomethylbenzylamino, 4-Cyanobenzylamino, 1-Benzhydrylazetidin-3-ylamino, 2,6-Dimethylpyridin-3-ylamino, 5-Cyanopyridin-2-ylamino, 1-Methylpiperidin-4-ylamino, 1-(Isopropyl)piperidin-4-ylamino, 1-(t-Butoxycarbonyl)piperidin-4-ylamino, 1-Benzoylpiperidin-4-ylamino, 1-(Pyridin-2-yl)piperidin-4-ylamino, 2-Piperidinoethylamino, 1,1-Dioxotetrahydrothiopyran-4-ylamino, Benzamido, Phenylacetamido, t-Butoxycarbonylamino, Methansulfonamido, n-Propylsulfonylamido, i-Propylsulfonylamido, n-Butylsulfonamido, 2-Methylprop-1-ylsulfonamido, 2,2-Dimethylprop-1-ylsulfonamido, 2-Methoxyethylsulfonamido, Phenylsulfonylamido, Benzylsulfonamido, 4-(Piperidin-4-yl)phenylsulfonylamido, 4-(1-Trifluoracetyl-
    Figure imgb0152
    Figure imgb0153
    Figure imgb0154
     oder eine entschützte Form davon, das heißt, worin P durch H ersetzt ist; und piperidin-4-yl)phenylsulfonylamido, Tetrahydropyran-4-ylmethylsulfonamido, 5-Methyl-1,2,3,4-tetrahydroisochinolin-8-ylsulfonylamido, 5-Methyl-2-trifluoracetyl-1,2,3,4-tetrahydroisochinolin-8-ylsulfonylamido, Benzylaminosulfonyl, 2-(N,N-Dimethylamino)ethoxy, Benzyloxy, 2-Piperidinoethoxy, 1-Methylpiperidin-4-yloxy, Phenylthio, Benzylthio oder Benzylsulfonyl ist oder 4-Isopropylpiperidinocarbonyl ist.
  23. Verbindung nach Anspruch 22, worin -A-R3 Phenylsulfonamido, Cyclohexylamino, 5-Methyl-1,2,3,4-tetrahydroisochinolin-8-ylsulfonylamido, 2-Methylprop-1-ylamino, i-Propylamino, 2-Methoxybenzylamino, N,N-(Diisopropyl)carbamoylmethylamino oder 2-Methylprop-1-ylsulfonamido ist.
  24. Pharmazeutische Zusammensetzung, die eine Verbindung der Formel (I) oder ein pharmazeutisch annehmbares Salz oder Solvat davon nach einem der vorhergehenden Ansprüche zusammen mit einem pharmazeutisch annehmbaren Exzipiens, Verdünnungsmittel oder Träger einschließt.
  25. Verbindung der Formel (I) oder ein pharmazeutisch annehmbares Salz, Solvat oder eine pharmazeutisch annehmbare Zusammensetzung davon nach einem der Ansprüche 1 bis 23 bzw. 24 zur Verwendung als Medikament.
  26. Verwendung einer Verbindung der Formel (I) oder eines pharmazeutisch annehmbaren Salzes, Solvates oder einer pharmazeutisch annehmbaren Zusammensetzung davon nach einem der Ansprüche 1 bis 23 bzw. 24 zur Herstellung eines entzündungshemmenden Mittels.
  27. Verwendung einer Verbindung der Formel (I) oder eines pharmazeutisch annehmbaren Salzes, Solvates oder einer pharmazeutisch annehmbaren Zusammensetzung davon nach einem der Ansprüche 1 bis 23 bzw. 24 zur Herstellung eines Medikamentes für die Behandlung einer Atemwegserkrankung.
  28. Verwendung nach Anspruch 27, wobei die Krankheit ausgewählt ist aus der Gruppe, bestehend aus Schocklunge (adult respiratory distress syndrome) (ARDS), Bronchitis, chronischer Bronchitis, chronisch-obstruktiver Lungenerkrankung, zystischer Fibrose, Asthma, Emphysemen, Bronchiektasie, chronischer Sinusitis und Rhinitis.
  29. Verwendung einer Verbindung der Formel (I) oder eines pharmazeutisch annehmbaren Salzes, Solvates oder einer pharmazeutisch annehmbaren Zusammensetzung davon nach einem der Ansprüche 1 bis 23 bzw. 24 zur Herstellung eines Medikaments für die Behandlung von septischem Schock, Funktionsstörung der männlichen Erektion, Hypertonie, Schlaganfall bzw. Iktus, Epilepsie, zerebraler Ischämie, peripherer Gefäßkrankheit, postischämischer Reperfusionsverletzung, Diabetes, Rheumatoider Arthritis, Multipler Sklerose, Psoriasis, allergischer Dermatitis, Ekzem, Colitis ulcerosa, Morbus Crohn, entzündlicher Darmerkrankung, Helicobacter pylori-Gastritis, nicht-Helicobacter pylori-Gastritis, durch nicht-steroidale Antirheumatika induzierte Schädigung des Gastrointestinaltraktes, Psychose oder zur Wundheilung.
  30. Verbindung der Formel
    Figure imgb0155
    Figure imgb0156
     worin q n-1 ist, Rd H oder Alkyl (vorzugsweise C1-C6-Alkyl) ist, P eine Schutzgruppe ist und R1, R2, R3, A und n wie in Anspruch 1 definiert sind.
  31. Verfahren zur Herstellung einer Verbindung der Formel (I) nach Anspruch 1 oder eines pharmazeutisch annehmbaren Salzes oder Solvates davon, das
    (a) für eine Verbindung der Formel (I), worin R1, R2, R3, A und n wie in Anspruch 1 definiert sind, die Entschützung einer Verbindung der Formel
    Figure imgb0157
     worin P eine Schutzgruppe ist und R1, R2, R3, A und n wie in Anspruch 1 definiert sind,
    (b) für eine Verbindung der Formel (I), worin A NRa, NRaC(O) , NRaC(O)NRa, NRaC(O)O oder NRaSO2 ist und Ra, R1, R2, R3 und n wie in Anspruch 1 definiert sind, die Umwandlung funktioneller Gruppen einer Verbindung der folgenden Formel
    Figure imgb0158
     worin R1, R2 und n wie in Anspruch 1 definiert sind, unter Verwendung eines geeigneten Reagenzes, wie ein Acylierungs-, Sulfonylierungs- oder Alkylierungsmittel, oder eines Dicarbonatderivates oder durch reduktive Aminierung, oder
    (c) für eine Verbindung der Formel (I), worin A NRaSO2, NRa, O oder S ist und Ra, R1, R2, R3 und n wie in Anspruch 1 definiert sind, die Umwandlung funktioneller Gruppen einer Verbindung der folgenden Formel
    Figure imgb0159
    worin R1, R2 und n wie in Anspruch 1 definiert sind, unter Verwendung eines geeigneten Reagenzes, wie ein Alkoxid, Thioalkoxid, Thiol, Sulfonamidderivat oder Amin,
    umfasst, wobei auf ein beliebiges der genannten Verfahren gegebenenfalls die Umwandlung der Verbindung der Formel (I) in ein pharmazeutisch annehmbares Salz davon folgt.
  32. Verbindung nach Anspruch 1, worin
    R1 Alkyl oder Cyclopropylmethyl ist;
    R2 Phenylalkylen oder Naphthylalkylen ist, worin die Alkylenkette mit Methyl, Ethyl, Phenyl oder Naphthyl substituiert sein kann;
    n 1 oder 2 ist; und
    A NRa, NRaC(O), NRaC (O) NRa, NRaC (O) O, OC (O) NRa, C (O) NRa, NRaSO2, SO2NRa O, S, oder SO2 ist, worin Ra H oder Alkyl ist;
    R3 eine Gruppe der Formel -(CH2)p-Rp-B ist, worin p 0, 1 oder 2 ist;
    Rp eine Bindung ist, oder Alkylen, gegebenenfalls alkylsubstituiertes Cycloalkylen, Phenylen oder Naphthylen, ist; und
    B (i) H, -NbRbRb, -ORb, -COORb, -OCORb, -SO2Rb, -CN, -SO2NRbRb, -NRbCORb oder -CONRbRb ist, in denen jedes Rb das gleiche oder verschieden ist und aus H und Alkyl ausgewählt ist, unter der Maßgabe, dass (a), wenn B -SO2Rb oder -NRbCORb ist, das terminale Rb dann nicht H ist und (b) Rp eine Bindung ist, p 0 ist und B H ist, nur wenn A NRa, NRaC (O) NRa, C (O) NRa, SO2NRa, O oder S ist, oder (ii) B eine gegebenenfalls substituierte, vollständig oder teilweise gesättigte oder ungesättigte mono- oder bicyclische, heterocyclische Gruppe ist, die durch ein Ringkohlenstoffatom gebunden ist,
    oder ein pharmazeutisch annehmbares Salz oder Solvat davon.
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GB9825383 1998-11-19
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GBGB9908931.0A GB9908931D0 (en) 1999-04-19 1999-04-19 Compounds
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Families Citing this family (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514949B1 (en) 1994-07-11 2003-02-04 University Of Virginia Patent Foundation Method compositions for treating the inflammatory response
US7427606B2 (en) 1999-02-01 2008-09-23 University Of Virginia Patent Foundation Method to reduce inflammatory response in transplanted tissue
US6232297B1 (en) 1999-02-01 2001-05-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
US7378400B2 (en) 1999-02-01 2008-05-27 University Of Virginia Patent Foundation Method to reduce an inflammatory response from arthritis
GB9924361D0 (en) 1999-10-14 1999-12-15 Pfizer Ltd Purine derivatives
GB9924363D0 (en) * 1999-10-14 1999-12-15 Pfizer Central Res Purine derivatives
GB0003960D0 (en) 2000-02-18 2000-04-12 Pfizer Ltd Purine derivatives
US6627785B1 (en) * 2000-02-29 2003-09-30 Virginia Commwealth University Wound dressings with protease-lowering activity
US6753322B2 (en) * 2000-06-06 2004-06-22 Pfizer Inc 2-aminocarbonyl-9H-purine derivatives
GB0014048D0 (en) * 2000-06-06 2000-08-02 Pfizer Ltd Purine derivatives
TWI227240B (en) * 2000-06-06 2005-02-01 Pfizer 2-aminocarbonyl-9H-purine derivatives
US6921753B2 (en) 2000-06-27 2005-07-26 Pfizer Inc Purine derivatives
GB0015727D0 (en) * 2000-06-27 2000-08-16 Pfizer Ltd Purine derivatives
GB0022695D0 (en) 2000-09-15 2000-11-01 Pfizer Ltd Purine Derivatives
US6670334B2 (en) 2001-01-05 2003-12-30 University Of Virginia Patent Foundation Method and compositions for treating the inflammatory response
EP1357908A4 (de) 2001-01-30 2009-07-15 Merck & Co Inc "acylsulfamide zur behandlung von fettleibigkeit, diabetes und lipidstörungen"
GB2372742A (en) * 2001-03-03 2002-09-04 Univ Leiden C2,5'-Disubstituted and N6,C2,5'-trisubstituted adenosine derivatives and their different uses
AU2002238748A1 (en) * 2001-03-12 2002-09-24 Glaxo Group Limited Pharmaceutical aerosol formulation
EP1395287A1 (de) * 2001-05-25 2004-03-10 Pfizer Inc. Adenosin-a2a-rezeptor-agonist und anticholinerges mittel in kombination zur behandlung von obstruktiven atemwegserkrankungen
US20030013675A1 (en) * 2001-05-25 2003-01-16 Boehringer Ingelheim Pharma Kg Combination of an adenosine A2A-receptor agonist and tiotropium or a derivative thereof for treating obstructive airways and other inflammatory diseases
WO2003029264A2 (en) * 2001-10-01 2003-04-10 University Of Virginia Patent Foundation 2-propynyl adenosine analogs having a2a agonist activity and compositions thereof
ATE381336T1 (de) * 2002-04-10 2008-01-15 Univ Virginia Verwendung von a2a adenosin rezeptor agonisten und anti-pathogene mittel enthaltenden kombinationen zur behandlung von entzündungskrankheiten
AR044519A1 (es) 2003-05-02 2005-09-14 Novartis Ag Derivados de piridin-tiazol amina y de pirimidin-tiazol amina
US20050033044A1 (en) * 2003-05-19 2005-02-10 Bristol-Myers Squibb Pharma Company Methods for preparing 2-alkynyladenosine derivatives
US20050059664A1 (en) * 2003-09-12 2005-03-17 Allergan, Inc. Novel methods for identifying improved, non-sedating alpha-2 agonists
GB0401334D0 (en) 2004-01-21 2004-02-25 Novartis Ag Organic compounds
TWI346109B (en) * 2004-04-30 2011-08-01 Otsuka Pharma Co Ltd 4-amino-5-cyanopyrimidine derivatives
US20050277615A1 (en) * 2004-05-17 2005-12-15 Can-Fite Biopharma Ltd. Pharmaceutical compositions having anti-inflammatory activity
GB0411056D0 (en) 2004-05-18 2004-06-23 Novartis Ag Organic compounds
DK1758596T3 (da) * 2004-05-26 2010-07-26 Inotek Pharmaceuticals Corp Purinderivater som adenosin-A1-receptoragonister og fremgangsmåder til anvendelse deraf
WO2006028618A1 (en) * 2004-08-02 2006-03-16 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs with modified 5'-ribose groups having a2a agonist activity
WO2006023272A1 (en) 2004-08-02 2006-03-02 University Of Virginia Patent Foundation 2-polycyclic propynyl adenosine analogs having a2a agonist activity
EP1778712B1 (de) 2004-08-02 2013-01-30 University Of Virginia Patent Foundation 2-propynyl-adenosin-analoga mit modifizierten 5'-ribosegruppen mit a2a-agonistenaktivität
US7863253B2 (en) * 2004-09-20 2011-01-04 Inotek Pharmaceuticals Corporation Purine Derivatives and methods of use thereof
GT200500281A (es) 2004-10-22 2006-04-24 Novartis Ag Compuestos organicos.
GB0424284D0 (en) 2004-11-02 2004-12-01 Novartis Ag Organic compounds
GB0426164D0 (en) 2004-11-29 2004-12-29 Novartis Ag Organic compounds
JP2008527003A (ja) * 2005-01-12 2008-07-24 キング・ファーマシューティカルズ・リサーチ・アンド・デベロプメント・インコーポレイティッド 喘息又は気管支痙攣の既往歴を有する患者における心筋機能不全を検出する方法
GB0500785D0 (en) 2005-01-14 2005-02-23 Novartis Ag Organic compounds
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
ES2358351T3 (es) * 2005-10-13 2011-05-09 Cv Therapeutics, Inc. Agonistas del receptor de adenosina a1.
US7910708B2 (en) 2005-10-21 2011-03-22 Novartis Ag Anti-IL13 human antibodies
CA2627319A1 (en) * 2005-11-30 2007-06-07 Prakash Jagtap Purine derivatives and methods of use thereof
GB0601951D0 (en) 2006-01-31 2006-03-15 Novartis Ag Organic compounds
US8795730B2 (en) * 2006-01-31 2014-08-05 David John Vachon Compositions and methods for promoting the healing of tissue of multicellular organisms
US8178509B2 (en) 2006-02-10 2012-05-15 University Of Virginia Patent Foundation Method to treat sickle cell disease
GB0607948D0 (en) * 2006-04-21 2006-05-31 Novartis Ag Organic compounds
KR20080110925A (ko) 2006-04-21 2008-12-19 노파르티스 아게 아데노신 ａ２ａ 수용체 효능제로서 사용하기 위한 퓨린 유도체
GB0607950D0 (en) 2006-04-21 2006-05-31 Novartis Ag Organic compounds
GB0607945D0 (en) * 2006-04-21 2006-05-31 Novartis Ag Organic compounds
US8188063B2 (en) 2006-06-19 2012-05-29 University Of Virginia Patent Foundation Use of adenosine A2A modulators to treat spinal cord injury
EP1889846A1 (de) 2006-07-13 2008-02-20 Novartis AG Purinderivate als A2a Agonisten
EP1903044A1 (de) 2006-09-14 2008-03-26 Novartis AG Adenosinderivate als Agonisten des A2A-Rezeptors
DE602007013441D1 (de) 2006-09-29 2011-05-05 Novartis Ag Pyrazolopyrimidine als pi3k-lipidkinasehemmer
CA2667962A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
US7897737B2 (en) 2006-12-05 2011-03-01 Lasergen, Inc. 3′-OH unblocked, nucleotides and nucleosides, base modified with photocleavable, terminating groups and methods for their use in DNA sequencing
WO2009061516A1 (en) * 2007-11-08 2009-05-14 New York University School Of Medicine Medical implants containing adenosine receptor agonists and methods for inhibiting medical implant loosening
US8058259B2 (en) 2007-12-20 2011-11-15 University Of Virginia Patent Foundation Substituted 4-{3-[6-amino-9-(3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid esters as A2AR agonists
PL2231642T3 (pl) 2008-01-11 2014-04-30 Novartis Ag Pirymidyny jako inhibitory kinazy
WO2009152353A2 (en) * 2008-06-11 2009-12-17 Lasergen, Inc. Nucleotides and nucleosides and methods for their use in dna sequencing
PT2391366E (pt) 2009-01-29 2013-02-05 Novartis Ag Benzimidazoles substituídos para o tratamento de astrocitomas
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
EP2464649A1 (de) 2009-08-12 2012-06-20 Novartis AG Heterocyclische hydrazonverbindungen und ihre verwendung zur behandlung von krebs und entzündung
NZ598220A (en) 2009-08-17 2014-02-28 Intellikine Llc Heterocyclic compounds and uses thereof
CA2771432A1 (en) 2009-08-20 2011-02-24 Novartis Ag Heterocyclic oxime compounds
SG10201502588UA (en) 2010-01-11 2015-05-28 Inotek Pharmaceuticals Corp Combination, kit and method of reducing intraocular pressure
MX2012010724A (es) 2010-03-26 2012-11-12 Inotek Pharmaceuticals Corp Metodo para reducir la presion intraocular en seres humanos empleando n6-ciclopentiladenosina (cpa), derivados de cpa o profarmacos de los mismos.
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
UY33597A (es) 2010-09-09 2012-04-30 Irm Llc Compuestos y composiciones como inhibidores de la trk
JP2014505088A (ja) 2011-02-10 2014-02-27 ノバルティス アーゲー Ｃ−ＭＥＴチロシンキナーゼ阻害剤としての［１，２，４］トリアゾロ［４，３−ｂ］ピリダジン化合物
JP5808826B2 (ja) 2011-02-23 2015-11-10 インテリカイン， エルエルシー 複素環化合物およびその使用
US9102671B2 (en) 2011-02-25 2015-08-11 Novartis Ag Compounds and compositions as TRK inhibitors
UY34329A (es) 2011-09-15 2013-04-30 Novartis Ag Compuestos de triazolopiridina
US9174994B2 (en) 2011-11-23 2015-11-03 Intellikine, Llc Enhanced treatment regimens using mTor inhibitors
US9278991B2 (en) 2012-01-26 2016-03-08 Inotek Pharmaceuticals Corporation Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)} methyl nitrate and processes of preparation thereof
CN104245701A (zh) 2012-04-03 2014-12-24 诺华有限公司 有酪氨酸激酶抑制剂的组合产品和其应用
US9381245B2 (en) 2012-10-19 2016-07-05 New York University Methods for inhibiting osteolysis
CN105188714A (zh) 2013-03-15 2015-12-23 伊诺泰克制药公司 眼用配制品
EP2968340A4 (de) 2013-03-15 2016-08-10 Intellikine Llc Kombination von kinaseinhibitoren und verwendungen davon
TW201605450A (zh) 2013-12-03 2016-02-16 諾華公司 Ｍｄｍ２抑制劑與ＢＲＡＦ抑制劑之組合及其用途
WO2016011658A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
KR20170036037A (ko) 2014-07-31 2017-03-31 노파르티스 아게 조합 요법
TW202140550A (zh) 2020-01-29 2021-11-01 瑞士商諾華公司 使用抗ｔｓｌｐ抗體治療炎性或阻塞性氣道疾病之方法

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003147A1 (en) * 1986-10-31 1988-05-05 Warner-Lambert Company Selected n6-substituted adenosines having selective a2 binding activity
GB2264948B (en) * 1992-03-13 1996-10-16 Merck & Co Inc Human adenosine receptors
US5877180A (en) * 1994-07-11 1999-03-02 University Of Virginia Patent Foundation Method for treating inflammatory diseases with A2a adenosine receptor agonists
US5859019A (en) * 1997-03-07 1999-01-12 Trustees Of The University Of Pennsylvania Methods for protecting against cardiac ischemia by administering adenosine A2a receptor antagonists
AU750322B2 (en) * 1997-05-09 2002-07-18 Trustees Of The University Of Pennsylvania, The Methods and compositions for reducing ischemic injury of the heart by administering adenosine receptor agonists and antagonists
CA2317093A1 (en) * 1998-01-08 1999-07-15 Joel M. Linden A2a adenosine receptor agonists
GB9813535D0 (en) * 1998-06-23 1998-08-19 Glaxo Group Ltd Chemical compounds
US6232297B1 (en) * 1999-02-01 2001-05-15 University Of Virginia Patent Foundation Methods and compositions for treating inflammatory response
GB9913932D0 (en) * 1999-06-15 1999-08-18 Pfizer Ltd Purine derivatives
ES2206259T3 (es) * 1999-06-22 2004-05-16 Cv Therapeutics, Inc. Agonistas del receptor a2a.
US6214807B1 (en) * 1999-06-22 2001-04-10 Cv Therapeutics, Inc. C-pyrazole 2A A receptor agonists
US6180615B1 (en) * 1999-06-22 2001-01-30 Cv Therapeutics, Inc. Propargyl phenyl ether A2A receptor agonists

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ATE331726T1 (de) 2006-07-15
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DE69932173T2 (de) 2007-06-06
WO2000023457A1 (en) 2000-04-27
EP1121372A1 (de) 2001-08-08
PE20001225A1 (es) 2000-11-07
DE69932173D1 (de) 2006-08-10
CO5450244A1 (es) 2004-10-29
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CA2347512C (en) 2005-12-06
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CA2347512A1 (en) 2000-04-27
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